Author(s): Koen van de Ven aff1 , Jannie Borst [*] aff1
antibody; cancer; co-inhibition; co-stimulation; cytotoxic T cell; immunotherapy; ipilimumab; nivolumab; TNF receptor family
The promise of cancer immunotherapy
The aim of cancer immunotherapy is to elicit a cytotoxic T-lymphocyte (CTL) response that eliminates all tumor cells, regardless of metastatic spread. One key approach is the use of so-called 'immunomodulatory' monoclonal antibodies (mAbs). Such mAbs do not directly target the tumor cells, but are directed at membrane receptors or ligands that regulate the T-cell response. Therapy with these mAbs aims to generate new tumor-specific CTLs from naive CD8+ T cells and to reactivate potentially pre-existing tumor-specific CTLs. The currently successful mAbs are meant to do this by blocking the interaction of the T-cell co-inhibitory receptors CTLA-4 and PD-1 with their respective ligands. Ipilimumab, which targets CTLA-4, was the first immunomodulatory mAb to be FDA approved, in this case for the treatment of patients with unresectable or metastatic melanoma [1 ]. In 2013, Wolchok et al . [2 ] reported their results from a clinical study in which stage IV melanoma patients were treated with ipilimumab in combination with nivolumab, a blocking mAb directed at PD-1 [3 ]. Response rates to monotherapy with ipilimumab or nivolumab were 10.9% [ 1 ] and 28% [3 ] respectively, but the response rate to combined therapy was 53% with a tumor reduction of more than 80% [2 ]. Inspired by this result, the journal Science proclaimed cancer immunotherapy as 'Breakthrough of the year 2013' [4 ].
The challenge is now to increase success rates of this immunotherapeutic approach and to extend it to other cancer types. To do this in a rational manner, the three major obstacles in raising T-cell immunity to cancer should be taken into account. These are: first, central tolerance, that is, deletion of self-reactive T cells during their development in the thymus. Since tumors are derived from our own cells, the available tumor-specific T-cell repertoire is limited and generally of low affinity. Second, peripheral tolerance. Tumors generally do not send out signals to activate dendritic cells (DCs) and without DC activation, the T-cell response will not be initiated. Third, cancer-associated immune suppression. The tumor cells, in dialogue with other (immune) cells in the tumor, create an immunosuppressive environment that counteracts CTL activity [5 ] (Figure 1).
Given the existence of central tolerance, the tumor types most eligible for immunotherapy are those carrying foreign antigens, such as virus-derived proteins and tumors with a high mutation load. Mutations potentially give rise to altered self-peptides (neoantigens) that can elicit a T-cell response. Efficacy of CTLA-4 and PD-1 blocking was demonstrated in melanoma and lung cancer that have a high mutation load [6 ] and are, therefore, expected to present neoantigens. Tumors may also present other antigens to which central tolerance is incomplete, such as cancer-testis antigens.
In immunogenic cancers, T-cell targeting immunotherapy should be aimed at overruling peripheral tolerance to tumor antigens and overruling cancer-associated immune suppression in a complementary fashion (Figure 1). Recent...